Aberrant remodelling of the retinal vasculature is a prominent feature of sight-threatening conditions such as diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, age-related macular degeneration and macular telangiectasia. These vascular changes manifest themselves as both new capillary growth from pre-existing retinal vessels (angiogenesis) and the development of vascular malformations of existing vessels (e.g., telangiectasia). This pathogenic vascular remodelling in these diseases is a major contributing factor to loss of vision.
Similar vascular pathology and dysfunction also accompanies tumour growth, where angiogenesis permits the enlargement and growth of solid tumours.
Substantial resource has been directed towards gaining an understanding of the mechanisms that drive these vascular responses (referred to as angiogenesis, neoangiogenesis, vascular proliferation, vascular remodelling, vascular pathology). Of the various molecules identified as playing an important role in the process, the vascular endothelial growth factors (VEGFs) and their receptors are viewed as critical components. Therapeutic targeting of the VEGF pathway in ocular angiogenesis using the anti-cancer agent Avastin® (or the closely related Lucentis) has resulted in improved clinical outcome, at least over the short term, of a number of sight-threatening conditions. However, there is concern over the long-term use of anti-VEGF strategies for the treatment of retinal vascular problems as VEGF has both neuroprotective activities and housekeeping roles such as the maintenance of choroidal fenestration. Moreover, although VEGF is considered to be the principal pro-angiogenic factor in neoangiogenesis, the process requires coordinated crosstalk between many factors, and the biological basis for other vascular changes, such as the formation of dilated and tortuous telangiectatic vessels, is not known.
There is therefore a need to identify alternative therapeutic targets and novel drugs which, in isolation or in combination with existing therapies, may be more effective and possess fewer off-target effects for the treatment of conditions where uncontrolled blood vessel growth and/or remodelling contributes to the disease.